Deep Brain Stimulation of the Cerebellar Dentate Nucleus to Enhance Chronic, Post-Traumatic Brain Injury Rehabilitation

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ABSTRACT The overall goal of this research is to develop and translate effective neurostimulation-based therapies to facilitate neurologic recovery for patients with chronic, persistent deficits secondary to acquired brain injury. Despite progress in acute intervention strategies, traumatic brain injury (TBI) remains a leading cause of long- term disability in the United States and there is an on-going need for novel approaches to facilitate recovery and rehabilitation for survivors. Our group has shown previously that deep brain stimulation (DBS) of the lateral cerebellar nucleus (LCN), the origin of the ascending dentatothalamocortical (DTC) pathway with widespread influence (via thalamus) across frontal and parietal cortical regions as well as to the basal ganglia, enhances motor rehabilitation in a chronic rodent model of middle cerebral artery ischemia. Therapeutic gains were associated with changes in perilesional cerebral cortical excitability, enhanced cerebral cortical reorganization, and evidence of increased synaptogenesis in perilesional cortex. Here, we will evaluate whether therapeutic benefit can be similarly realized for persistent motor and cognitive deficits following TBI, using a controlled cortical impact (CCI) model in rodents. Moreover, we will further characterize the LCN DBS-induced physiological and cellular changes that occur across perilesional cortical regions. In addition to the supporting evidence afforded by our prior work in rodent models of middle cerebral artery ischemia and our early results from human translation of that work, we provide preliminary evidence of behavioral efficacy and underlying physiological mechanisms in two treatment models: rats with induced motor deficits following fluid percussion injury (FPI) TBI over sensorimotor cortex as well as animals that showed cognitive deficits following bi-frontal CCI targeting medial prefrontal cortical regions. In the current proposal, our specific aims are 1) to confirm and extend our preliminary findings regarding LCN DBS' effects on post-TBI motor recovery, 2) to evaluate the potential LCN DBS to improve post-TBI cognitive function, 3) to characterize the nature of LCN DBS-mediated perilesional and DTC pathway reorganization post-CCI injury; and 4) to examine the cellular and molecular changes in perilesional cortical regions associated with LCN DBS. This study will provide preclinical evidence and support for future translational efforts of this novel therapeutic approach to enhancing chronic, post-TBI deficits.